BESINS HEALTHCARE SYMPOSIUM 30Th Annual ESHRE Meeting, Munich, Germany

BESINS HEALTHCARE SYMPOSIUM 30th Annual ESHRE Meeting, Munich, Germany

Worldwide, one in six couples experience some form of infertility problem at least once during their reproductive lifetime.1 Implantation failure is a common cause of infertility.2 For some patients, this can occur repeatedly even under ideal conditions.3 Recent progress in research and clinical practices to overcome challenges in Assisted Reproductive Technology (ART) were discussed at the Besins Healthcare symposium at the ESHRE 2014 annual meeting, 30 July 2014. Chaired by the esteemed Prof. Johan Smitz (Belgium) and Prof. Franz Geisthövel (Germany), experts in the field provided insights on the role of natural hormones such as progesterone, oestradiol and testosterone in the prevention of implantation failure.

The recent ESHRE 2014 annual meeting held in Munich, Germany from 29 June – 2 July, provided a forum to exchange and discuss new clinical and scientific ideas in the field of reproductive medicine.

Optimising Luteal Phase Support

with Vaginal Progesterone from

Conception until Delivery

Professor William Ledger

Australia

Overview: Progesterone supplementation has been used to treat those with threatened miscarriage and premature labour.4-5 However, the literature in this field, of variable quality, yield conflicting results. Recent systematic reviews and meta-analyses suggest that progesterone has a beneficial role for the treatment of women with recurrent pregnancy failure or with signs of risk of premature labour.6-7 Better designed, well-powered trials are still needed before a consensus can be reached.

Implantation: Secretion of progesterone by the corpus luteum is essential for implantation and successful early pregnancy.2 The luteal phase in the ART-stimulated cycles is different from the natural one and luteal phase support (LPS) is necessary for successful implantation.6-7

LPS is required irrespective of whether a gonadotropin- releasing hormone (GnRH) agonist or antagonist protocol is used.6,8-10 Historically, LPS has employed human chorionic gonadotropin (hCG), progesterone or both. Given the decreased risk of ovarian hyperstimulation syndrome (OHSS) and similar incidence in the live birth and clinical pregnancy rates (CPR), LPS with progesterone alone would be favoured for straightforward patients rather than using an hCG-containing regimen.6,9

Ninety nine percent of IVF centres reported they use progesterone for LPS (Figure 1).8 Comparable efficacy in CPR, ongoing pregnancy rates (OPR) and live births have been demonstrated when intramuscular (IM) or vaginal routes of administration were used.8 Given the additional pain and discomfort which may be associated with IM injection, vaginal progesterone may be preferable for patients. In all, 77% of cycles in IVF clinics reported using vaginal progesterone alone.8

In women receiving their vitrified blastocysts through frozen embryo transfer (FET), equivalent CPR and live birth rates were reported for both vaginal and IM progesterone administered in combination with oestrogen as part of their LPS.11

GnRH agonist (GnRHa) triggers have been used in clinics to avoid OHSS.10,12-16 Although the risk of OHSS is reduced with this approach, the pregnancy rates are significantly lower after fresh embryo transfer (ET) if normal LPS is used.12-16 The endometrial effect of progesterone is demonstrated by the excellent pregnancy rates when donor eggs are used in ET after agonist trigger, without any requirement for additional LPS.17

When performing fresh ET, LPS support after GnRHa trigger shows:

• Steroids in combination with progesterone and transdermal (TdL) oestradiol reduce the risk of OHSS with OPR comparable to hCG.16

• That an intensive treatment with low dose hCG, IM progesterone, vaginal progesterone and oestradiol valerate (E2V) produces good CPR but does not completely eradicate OHSS in the high risk patients.18-19

Based on IVF-Worldwide survey 2013,8,20 no clear preferred protocol was identified. There was no consensus for luteal phase management with freeze-all (43%), support with steroids plus hCG (26%) and intensive steroids alone (31%) approaches being similarly reported.20

The optimal duration for progesterone administration varies across the literature. Recently, small trials indicate that it could be feasible to stop progesterone treatment at the point of confirmed pregnancy (as the body will be producing more progesterone in the pregnant state), but further investigations are required.21

First trimester: A Cochrane analysis indicated that progesterone may be beneficial in reducing the risk of miscarriage.22 However, this was not a conclusive finding due to limitations in the available data used for this meta-analysis.

The PROgesterone in recurrent MIScarriage (PROMISE; Figure 2) study is investigating the role of progesterone in preventing miscarriages in patients who have experienced recurrent (more than three consecutive) miscarriages.23-24 The study was fully recruited, and preliminary results will be available by October 2014.

Even with the PROMISE data, a knowledge gap will remain for any benefit progesterone may offer for patients have some spotting or bleeding in early pregnancy.

Established pregnancy: In established pregnancy, the importance of the corpus luteum production of progesterone in a successful pregnancy has been established for some time.25,26

Administration of vaginal progesterone for singleton pregnancies with a sonographic asymptomatic short cervix in the mid-trimester showed a significant reduction of 42% in the rate of preterm birth <33 weeks and reduced risk of neonatal morbidity and mortality.27 Rouse et al. showed that 17 alpha-hydroxyprogesterone caproate (17P) had no effect on the rate of premature birth versus a placebo control with twins.28 Progesterone helps to slow down cervical shortening and onset of premature labour in asymptomatic patients with singleton pregnancies, and may justify a case for screening all or at risk patients.29

Most scientific societies recommend vaginal progesterone in women with a sonographic short cervix measured at mid- trimester and/or a history of previous spontaneous preterm birth, although there is disparity on the cervical length before initiation of treatment.30-33 Debate remains about the role of routine screening and the US FDA, UK Royal College of Obstetricians and Canadian Society of Obstetricians and Gynecologists all suggest that women at risk of should be encouraged to enrol in trials of progesterone. However, there remains a hurdle in recruitment for trials where the patient may receive a placebo.

The potential effects of vaginal micronised progesterone capsules on preventing preterm birth, and any long term neonatal or infant benefits, are being investigated in the OPPTIMUM study (Figure 3).34

Currently, the quality of data for making informed decisions on the correct protocol for patients are somewhat lacking and additional well-designed, adequately-powered, placebo-controlled studies are necessary to ensure optimal patient treatment.

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